WldS Enhances Insulin Transcription and Secretion via a SIRT1-Dependent Pathway and Improves Glucose Homeostasis

OBJECTIVE Wld S (Wallerian degeneration slow), a fusion protein from a spontaneous mutation containing full-length nicotinamide mononucleotide adenylyltransferase 1, has NAD biosynthesis activity and protects axon from degeneration robustly. NAD biosynthesis is also implicated in insulin secretion in β-cells. The aim of this study was to investigate the effect of Wld S on β-cells and glucose homeostasis. RESEARCH DESIGN AND METHODS Using the Wld S mice, we measured the expression of Wld S in pancreas and analyzed the effect of Wld S on glucose homeostasis. The direct effect of Wld S on insulin transcription and secretion and the related mechanisms was measured in isolated islets or β-cell lines. Silent information regulator 1 (SIRT1), an NAD-dependent protein deacetylase, is involved in insulin secretion. Thus, Wld S mice with SIRT1 deficiency were generated to study whether the SIRT1-dependent pathway is involved. RESULTS Wld S is highly expressed in the pancreas and improves glucose homeostasis. Wld S mice are resistant to high-fat diet–induced glucose intolerance and streptozotocin (STZ)-induced hyperglycemia. Wld S increases insulin transcription dependent on its NAD biosynthesis activity and enhances insulin secretion. SIRT1 is required for the improved insulin transcription, secretion, and resistance to STZ-induced hyperglycemia caused by Wld S . Moreover, Wld S associates with SIRT1 and increases NAD levels in the pancreas, causing the enhanced SIRT1 activity to downregulate uncoupling protein 2 (UCP2) expression and upregulate ATP levels. CONCLUSIONS Our results demonstrate that Wld S combines an insulinotropic effect with protection against β-cell failure and suggest that enhancing NAD biosynthesis in β-cells to increase SIRT1 activity could be a potential therapeutic approach for diabetes.